Background: Very few studies have investigated the association between total plasma homocysteine (tHcy) and depressive symptoms in older Hispanics. Objective: To test the hypothesis that high tHcy associates with depressive symptoms in older Hispanics. Methods: A total of 1,418 participants .55 years old from the Maracaibo Aging Study (MAS) underwent standardized neurological, neuropsychiatric, and cardiovascular assessments. The Neuropsychiatric Inventory Depression Subscale (NPId) was used to assess the burden of depressive symptoms. The tHcy levels and other biochemical parameters in blood samples were measured. Univariate and multivariate logistic regression models were applied. Results: Participants with depressive symptoms had higher levels of tHcy than those without (15.1 versus 13.9 µmol/L; p = 0.009). Elevated tHcy levels were associated with depressive symptoms after adjusting for age, sex, education, smoking, diabetes, hypertension, alcohol intake, stroke, and dementia (OR = 1.58; 95% CI, 1.18–2.12). Conclusion: Elevated levels of tHcy were associated with depressive symptoms in older Hispanics living under the nutritional and environmental conditions of a developing country.